Modified Project Summary/Abstract Section: RO1 MH095380 Novel targets need to be identified to develop new therapies for depression, a prevalent and debilitating disease often not adequately treated. The immune system is one such novel target, as substantial evidence demonstrates its involvement in depression. While previously the CNS was considered insulated from the immune system, it is now well-established that immune cells in the CNS modulate multiple processes, such as neurogenesis and cognition. The immune system includes a rapid-response innate immune system that produces cytokines and chemokines that activate and recruit the adaptive immune system, which includes T cells that possess the capacity of memory. Many CNS functions, such as cognition and mood, are affected by cytokines, but less is known about the regulation and functional effects of T cells in the CNS associated with depression. The overall hypothesis of this project is that T cells have subtype-specific regulatory effects on the susceptibility to depression and responses to antidepressants. We will examine the influences of T cell subtypes on susceptibility to depressive-like behavior, and examine the role of glycogen synthase kinase-3 (GSK3) as a regulatory mechanism linking immune responses with susceptibility to depression. These goals will identify new mechanisms by which the adaptive immune system may contribute to depression and be a novel target for therapeutic intervention. Specific Aim 1 will test the hypothesis that T cell subtype-selective actions in the brain modify depressive-like behavior. T cell depletion and transfer approaches will be used to identify consequences of T cell subtypes on susceptibility to depression-like behavior. Our Preliminary Results show accumulation of inflammatory Th1 and Th17 cells in the brains of mice exhibiting depression-like behavior, that Th1 cell depletion exacerbates depression-like behavior, that Th17 cell depletion ameliorates depression-like behavior, and that Treg repletion has antidepressant effects. Specific Aim 2 will test the hypothesis that glycogen synthase kinase-3 (GSK3) is a critical link between immune activation and susceptibility to depressive-like behavior. Our Preliminary Results show that mice expressing constitutively active GSK3 (GSK3 knockin mice) display increased susceptibility to depression-like behavior and that GSK3 drives the production of inflammatory Th17 cells. Because GSK3 promotes depression-like behavior, is linked to human depression, regulates the generation of T cell subtypes, and promotes inflammatory responses, we will apply molecular and pharmacological manipulations of GSK3 to test if GSK3's immune effects contribute to its promotion of susceptibility to depression.